Summary of work: We continue to elucidate the mechanisms by which D2 dopamine (DA) receptors, and the neurons which contain them, are lost during normal aging, resulting in impaired motor control. In our neonatal rat neuron culture model, DA induced killing has been blocked with D2 receptor antagonists as well as antioxidants, suggesting that both signal transduction mechanisms and spontaneous antioxidation of DA may be responsible. The signal transduction avenue has been further implicated by use of 293 cells as well as the primary neuron cultures. In both systems, DA appears to work through the JNK pathway to induce apoptotic death, which additionally can be prevented by antioxidants. We also continue to elucidate the mechanisms by which G protein mediated signal transduction is impaired during aging. Previously reported alterations in striatal muscarinic receptor - G protein cycling, have been further validated by the observations of an age related decrease in the molecular mass of the receptor - G protein complexes when analyzed by sucrose denoted gradients and subsequent immunoblotting. This suggests that a higher proportion of receptors may exist in the uncoupled state in the aged striata. Implications of altered G protein cycling for Alzheimer's Disease have also been extended using a cultured neuron system which exhibits similar impairment following exposure to amyloid beta peptide. In collaboration with Dr. Mark Mattson, we have recently shown that 4-hydroxynonenol, a highly reactive aldehyde byproduct of oxyradical induced membrane lipid peroxidation, may mediate this effect. Like the DA induced neuronal death reported above, this effect can be prevented by preincubation with antioxidants.